Abstract
Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs.
Highlights
Nicotinic receptors are activated by acetylcholine and have been implicated in several neurological disorders
Nineteen compounds were synthesized that share close chemical similarity to one another but form a series containing all possible combinations of methyl substitution on a single aromatic ring (Fig. 1)
Activation by the methyl-substituted compounds resulted in responses that were similar to responses with allosteric agonists of ␣7 Nicotinic acetylcholine receptors (nAChRs) examined previously [17, 24, 35]
Summary
Nicotinic receptors are activated by acetylcholine and have been implicated in several neurological disorders. An area that has attracted considerable interest concerns compounds that lack intrinsic agonist activity on nAChRs but are able to potentiate agonist-evoked responses by binding to a distinct allosteric site Such compounds have been described as positive allosteric modulators (PAMs) and include compounds such as TQS, a PAM that displays selectivity for ␣7 nAChRs [15]. Whereas previous studies of compounds with close chemical similarity to TQS have identified only allosteric agonists or type II PAMs [15, 17, 24], studies conducted with this series of 19 methyl-substituted compounds have revealed five distinct pharmacological effects on ␣7 nAChRs. In summary, the 19 methyl-substituted compounds examined in this study can be classified in one of five categories: allosteric agonists, type I PAMs, type II PAMs, negative allosteric modulators (NAMs), or silent allosteric modulators (SAMs)
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